title: Sts-2 is a phosphatase that negatively regulates zeta-associated protein (ZAP)-70 and T cell receptor signaling pathways.
abstract: T cell activity is controlled in large part by the T cell receptor (TCR). The TCR detects the presence of foreign pathogens and activates the T cell-mediated immune reaction. Numerous intracellular signaling pathways downstream of the TCR are involved in the process of T cell activation. Negative regulation of these pathways helps prevent excessive and deleterious T cell responses. Two homologous proteins, Sts-1 and Sts-2, have been shown to function as critical negative regulators of TCR signaling. The phosphoglycerate mutase-like domain of Sts-1 (Sts-1(PGM)) has a potent phosphatase activity that contributes to the suppression of TCR signaling. The function of Sts-2(PGM) as a phosphatase has been less clear, principally because its intrinsic enzyme activity has been difficult to detect. Here, we demonstrate that Sts-2 regulates the level of tyrosine phosphorylation on targets within T cells, among them the critical T cell tyrosine kinase Zap-70. Utilizing new phosphorylated substrates, we demonstrate that Sts-2(PGM) has clear, albeit weak, phosphatase activity. We further pinpoint Sts-2 residues Glu-481, Ser-552, and Ser-582 as specificity determinants, in that an Sts-2(PGM) triple mutant in which these three amino acids are altered to their counterparts in Sts-1(PGM) has substantially increased activity. Our results suggest that the phosphatase activities of both suppressor of TCR signaling homologues cooperate in a similar but independent fashion to help set the threshold for TCR-induced T cell activation.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Boris
authors.initials: B
authors.lastname: San Luis
authors.forename: Ben
authors.initials: B
authors.lastname: Sondgeroth
authors.forename: Nicolas
authors.initials: N
authors.lastname: Nassar
authors.forename: Nick
authors.initials: N
authors.lastname: Carpino
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D017027:Protein Tyrosine Phosphatases; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013379:Substrate Specificity / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D011948:Receptors, Antigen, T-Cell; C482177:Sts-2 protein, mouse; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse; D010749:Phosphoprotein Phosphatases; D017027:Protein Tyrosine Phosphatases; C553497:TULA-2 protein, mouse